-arrestins were initially discovered to desensitize GPCR signaling in response to agonist stimulation. However, it is now appreciated that -arrestins can also transduce multiple effector pathways independent of G-protein signaling when receptors are stimulated by certain ligands, a concept known as biased signaling. The proposed mechanism for this signaling bias is based on the barcode hypothesis where unbiased and -arrestin-biased ligands impart distinct patterns of receptor phosphorylation by specific GPCR kinases (GRKs), thus converting a distinct ligand stabilized receptor conformation into selective -arrestin function and downstream signaling. In this proposal we plan to discover new mechanistic insights for the precise molecular details that underlie -arrestin biased signaling and determine how this may influence cardiac function. We will use a mass spectrometry phosphoproteomic based approach to determine whether Carvedilol induces a unique phosphorylation bar code of the 1AR compared to the balance agonist isoproterenol, and will translate these findings in vivo by using mice conditionally lacking -arrestin in differnt cell types of the heart and determine the effect of -arrestin bias on the transcriptional signatue and cardiac function under normal and injured conditions. We propose the following specific aims: Aim 1: Determine the specific phosphorylation bar code on the c-terminal tail of 1AR responsible for G?i dependent -arrestin-biased signaling. Aim 2: Determine the mechanism of 1AR-biased signaling in cardiac fibroblasts. Aim 3: Determine the cardiac cell type responsible for -arrestin signaling that promotes cardiac fibrosis in response to injury. Aim 4: Determine th cell-type specific RNA signature of wild type and conditionally deleted -arrestin1 and 2 KO mice in response to the biased ligand carvedilol and after cardiac injury.